Heart failure is the leading cause of death in the elderly. However, it is unclear whether this is the result of a primary aging cardiomyopathy or the consequence of chronic coronary artery disease. In humans, it is difficult to separate the inevitable pathology of the coronary circulation with age from the intrinsic mechanisms of myocardial aging and heart failure. The aging heart typically shows a decreased functional reserve and limited capacity to adapt to cardiac diseases (Maggioni et al. (1993) N. Engl. J. Med. 329: 1442-1448). An important question is whether average lifespan reflects the ineluctable genetic clock (Sanderson and Scherbov (2005) Nature 435: 811-813) or heart failure interferes with the programmed death of the organ and organism negatively affecting lifespan in humans.
Cardiovascular disease is one possible cause of heart failure and a major health risk throughout the industrialized world. Atherosclerosis, the most prevalent of cardiovascular diseases, is the principal cause of heart attack, stroke, and gangrene of the extremities, and thereby the principal cause of death in the United States. Atherosclerosis is a complex disease involving many cell types and molecular factors (for a detailed review, see Ross (1993) Nature 362: 801-809).
Ischemia is a condition characterized by a lack of oxygen supply in tissues of organs due to inadequate perfusion. Such inadequate perfusion can have a number of natural causes, including atherosclerotic or restenotic lesions, anemia, or stroke, to name a few. Many medical interventions, such as the interruption of the flow of blood during bypass surgery, for example, also lead to ischemia. In addition to sometimes being caused by diseased cardiovascular tissue, ischemia may sometimes affect cardiovascular tissue, such as in ischemic heart disease. Ischemia may occur in any organ, however, that is suffering a lack of oxygen supply.
The most common cause of ischemia in the heart is myocardial infarction (MI). Commonly known as a heart attack, MI is one of the most well-known types of cardiovascular disease. 1998 estimates show 7.3 million people in the United States suffer from MI, with over one million experiencing an MI in a given year (American Heart Association, 2000). Of these individuals, 25% of men, and 38% of females will die within a year of their first recognized MI (American Heart Association, 2000). MI is caused by a sudden and sustained lack of blood flow to an area of the heart, typically caused by narrowing of a coronary artery. Without adequate blood supply, the tissue becomes ischemic, leading to the death of myocytes and vascular structures. This area of necrotic tissue is referred to as the infarct site, and will eventually become scar tissue. Survival is dependent on the size of this infarct site, with the probability of recovery decreasing with increasing infarct size. For example, in humans, an infarct of 46% or more of the left ventricle triggers irreversible cardiogenic shock and death.
Most studies on MI have focused on reducing infarct size. There have been a few attempts to regenerate the necrotic tissue by transplanting cardiomyocytes or skeletal myoblasts (Leor et al. (1996) Circulation 94:(Supplement II) II-332-II-336; Murray et al. (1996) Clin. Invest. 98:2512-2523; Taylor et al. (1998) Nature Med. 4, 929-933; Tomita et al. (1999) Circulation 100(suppl II), II-247-II-256; Menasche et al. (2000) Circulation 100(suppl II), II-247-II-256). While the cells may survive after transplantation, they fail to reconstitute healthy myocardium and coronary vessels that are both functionally and structurally sound.
All of the cells in the normal adult originate as precursor cells which reside in various sections of the body. These cells, in turn, derive from very immature cells, called progenitors, which are assayed by their development into contiguous colonies of cells in 1-3 week cultures in semisolid media such as methylcellulose or agar or liquid media. Progenitor cells themselves derive from a class of progenitor cells called stem cells. Stem cells have the capacity, upon division, for both self-renewal and differentiation into progenitors. Thus, dividing stem cells generate both additional primitive stem cells and somewhat more differentiated progenitor cells. In addition to the well-known role of stem cells in the development of blood cells, stem cells also give rise to cells found in other tissues, including but not limited to the liver, brain, and heart.
Stem cells have the ability to divide indefinitely, and to specialize into specific types of cells. Totipotent stem cells, which exist after an egg is fertilized and begins dividing, have total potential, and are able to become any type of cell. Once the cells have reached the blastula stage, the potential of the cells has lessened, with the cells still able to develop into any cell within the body, however they are unable to develop into the support tissues needed for development of an embryo. The cells are considered pluripotent, as they may still develop into many types of cells. During development, these cells become more specialized, committing to give rise to cells with a specific function. These cells, considered multipotent, are found in human adults and referred to as adult stem cells. It is well known that stem cells are located in the bone marrow, and that there is a small amount of peripheral blood stem cells that circulate throughout the blood stream (National Institutes of Health, 2000).
To date, with the exception of a few hematological disorders (Bagby et al. (2004) Hematology Am. Soc. Hematol. Educ. Program 318-336), stem cell failure does not occur in self-renewing organs including the human heart. Pools of functionally competent cardiac stem cells are present in the heart of patients who die acutely after a large myocardial infarct or undergo cardiac transplantation for end-stage ischemic and non-ischemic cardiomyopathy (Urbanek et al. (2003) Proc. Natl. Acad. Sci. USA 100, 10440-10445; Urbanek et al. (2005) Proc. Natl. Acad. Sci. USA 102, 8692-8697). Similarly, cycling cardiac stem cells with long telomeres have been identified in the old decompensated human heart in the absence of risk factors of coronary artery disease and cardiac failure (Chimenti et al. (2003) Circ. Res. 93: 604-613).